KR20090024140A - Treatment for depressive disorders - Google Patents

Abstract

A method of treating depression comprising administering a melatonin agonist.

Description

Treatment for Depressive Diseases {TREATMENT FOR DEPRESSIVE DISORDERS}

This application claims priority to US provisional patent application 60 / 747,843, which is hereby incorporated by reference in its entirety and filed on May 22, 2006.

The present invention relates to the field of drug treatment for depressive diseases.

Depressive diseases affect nearly 20 million adults in the United States alone. If left untreated, depressive illness can be debilitating not only emotionally but also physically.

Depressive diseases include a series of symptoms, which are listed in a book entitled "Depression" published by the National Institute of Mental Health (NIMH), as follows:

“Continuous sadness, worry or“ empty ”mood

Feeling hopeless, pessimism

Guilt, worthlessness, helplessness

Loss of interest or pleasure in past hobbies or activities, including libido

Vitality, fatigue, "slowing down"

Difficulty concentrating, remembering, and making decisions

Insomnia, wheezing at dawn or oversleeping

Appetite and / or weight loss or overeating and weight gain

Thoughts of death or suicide; Suicide attempt

Not calm, impatient

Persistent physical symptoms that do not respond to treatment, such as headaches, digestive problems, and chronic pain

According to the NIMH booklet, the three most common types of depressive disorder are:

Major depression is evident by a combination of symptoms (see symptom list) that interferes with the ability to work, study, sleep, eat, and enjoy pleasant activities. This episode of depression may occur only once, but more commonly occurs several times in life.

Dysthymia, a less severe type of depression, includes long-term chronic symptoms that do not help but do not live well or feel good. Many people with dysthymia also experience major depression episodes at some time in their lives.

Another type of depression is bipolar disorder, also called manic-depressive disease. Not as common as other forms of depressive disorder, manic depression is characterized by repeated changes in mood, namely very good (manic) and bad (depression). Sometimes, mood swings are dramatic and fast, but most are gradual. When in the depression cycle, an individual may have some or all of the symptoms of a depressive disorder. When in the manic cycle, an individual may be overactive, over chattering and full of energy. Manic affects thinking, judgment, and social behavior in ways that often lead to serious problems and embarrassment. For example, an individual in a manure may feel full of encouraging, grand schemes that can range from unwise business decisions to romantic sprees. If mania is left untreated, it can go bad to mental illness.

The compound referred to herein as MA-1 is (1R-trans) -N-[[2- (2,3-dihydro-4-benzofuranyl) cyclopropyl] methyl] propanamide. MA-1 is an experimental melatoninic agonist with high affinity for both melatonin-1 (MT1) and melatonin-2 (MT2) receptors, and therefore is a critical component of insomnia and circadian rhythm sleep disorders. Potentially useful for treatment. MA-1 is disclosed in US Pat. No. 5,856,529, the entire contents of which are incorporated herein by reference. The compound referred to herein as MA-2 is N-[[2- (2,3-dihydro-4-benzofuranyl) cyclopropyl] methyl] propanamide (referred to herein as "MA-1"), N- [1- (2,3-dihydrobenzofuran-4-yl) pyrrolidin-3-yl] -N-ethylurea]. MA-2 is also an experimental melatoninic agonist, the entire contents of which are disclosed in US Pat. No. 6,211,225, which is incorporated herein by reference.

The methods of the present invention include treating one or more symptoms of depressive disorders as well as treating one or more depressive disorders in an animal.

The present invention also includes treating or preventing other diseases in which certain antidepressants, such as serotonin reuptake inhibitors, have been shown to be useful. These include, but are not limited to, obsessive-compulsive disorder, panic disorder, social anxiety disorder, social phobia, post-traumatic stress disorder, premenstrual anxiety disorder, and general anxiety disorder.

The present invention is described hereinafter with reference to exemplary embodiments, the melatonin agonists referred to herein as MA-1 and MA-2, and salts, prodrugs, esters, metabolites, soluble compounds thereof. It relates to the use of solvates, hydrates, enantiomers, stereoisomers and amorphous and crystalline forms. MA-1 is a white to off-white powder having a melting point of about 78 ° C. (DSC), and has a structure represented by Formula 1.

As metabolites of MA-1, for example, the "new melatonin receptor efficacy of J. Pharmaceutical Sci., 92 (4): 760-772 by Vachharajani et al., Incorporated herein by reference in its entirety. And preclinical pharmacokinetics and metabolism of Jane BMS-214778. More specifically, these metabolites include glucuronide and diol derivatives of MA-1 as well as hydroxylated and dehydrogenated derivatives of MA-1. Eight of these metabolites have the structures shown in Formulas 2-9.

An effective amount of MA-1 or MA-2 may be administered in a number of routes to a subject animal (typically human, but other animals such as livestock, pets and racing animals may also be processed). have. An effective amount is an amount that has the effect of preventing or ameliorating a depressive disease or symptom during treatment. For example, an effective amount is an amount that prevents the onset or recurrence of depressive disease symptoms to the same extent as other antidepressants, such as selective serotonin reuptake inhibitors such as fluoxetine, paroxetine, sertraline and the like.

The effective amount may vary quantitatively depending on, for example, the patient, the severity of the disease or condition being treated and the route of administration. This dose can be determined by routine studies. In general, for systemic administration such as, for example, oral administration, the reference point of the dose is the dose of MA-1 or MA-2, ie oral administration, used to treat circadian rhythm diseases in humans. Hour 1 to 500 mg / day. MA-1 or MA-2 is expected to be administered to adults in doses of 1 to 500 mg / day, but low doses such as 150, 100, 50, 25, 10 or 1 mg / to prevent possible side effects. It is preferable to use work. In general, the dosage of MA-1 will be in the range of about 10 to about 150 mg / day, preferably about 10 to about 100 mg / day in one or more unit dosage forms.

Dosage protocols involving the amount of MA-1 or MA-2 actually administered are related, including, for example, the condition being treated of an individual patient, the route of administration chosen, age, weight, response and degree of symptoms of the patient. It will be appreciated that it may be determined by the physician in light of the environment. Of course, patients should be monitored for possible side effects.

For therapeutic or prophylactic purposes, MA-1 or MA-2 is a solid or liquid pharmaceutically acceptable carrier and, optionally, combined with at least one of these compounds as essential active ingredients, usually by introducing conventional techniques of the standard. It will be administered in a pharmaceutical composition comprising a pharmaceutically acceptable adjuvant and excipient.

MA-1 is highly soluble or freely soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycol (PEG-300 and PEG-400) and only slightly soluble in water. The inherent pH of the MA-1 solution saturated in water is 8.5 and its water solubility is substantially unaffected by the pH.

Pharmaceutical compositions useful in the practice of the present invention include dosage forms suitable for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous), transdermal, bronchial or intranasal administration. Thus, if a solid carrier is used, the preparation may be in tablets, in the form of powder or pellets in hard gelatin capsules, or in the form of troches or lozenges. The solid carrier may comprise conventional excipients such as binders, fillers, tablet lubricants, disintegrants, wetting agents and the like. The tablet may be a film coated by conventional techniques, if necessary. When a liquid carrier is introduced, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, aqueous solution or non-aqueous suspension, or be reconstituted with water or other suitable carrier before use. May be a dry product. Liquid formulations may include conventional additives such as suspending agents, emulsifiers, wetting agents, non-aqueous carriers (including cooking oil), preservatives as well as flavoring and / or coloring agents. For parenteral administration, the carrier will usually comprise at least a substantial portion of sterile water, although physiological saline solutions, glucose solutions, and the like may be used. Injectable suspensions may also be used, in which case conventional suspensions may be incorporated. Conventional preservatives, buffers and the like can also be added to the parenteral dosage forms. It is particularly useful that the compound of formula 1 is administered in an oral dosage form. Such pharmaceutical compositions may be prepared by conventional techniques suitable for the desired formulation comprising an appropriate amount of MA-1 or MA-2. See, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.

In preparing a pharmaceutical composition for use in the present invention, the active ingredient (s) is usually mixed with the carrier, diluted by the carrier, or contained within the carrier, and may be in capsules, sachets, paper or other containers. It may be in the form of. When the carrier acts as a diluent, the carrier may be a solid, semisolid or liquid substance and acts as a carrier, excipient or medium for the active ingredient. Thus, the composition can be used in tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid medium), for example the activity In the form of ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing up to 10% by weight of the compound.

Some examples of suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, Cellulose, water, syrup, methyl cellulose, methyl- and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulation may further comprise lubricants, wetting agents, emulsifiers and suspending agents, preservatives, sweeteners or flavoring agents. Compositions of the present invention may be formulated to provide fast, sustained or delayed release of the active ingredient after administration to a patient.

The composition is formulated in unit dosage form, each dosage preferably comprising about 0.1 to about 100 mg of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable for a single dose for human subjects and other mammals, each unit calculated to produce the desired prophylactic or therapeutic effect over the course of treatment with the required pharmaceutical carrier. A predetermined amount of the active substance. Thus, for example, an adult patient with a depressive disease may be prescribed to be administered once, twice or three times daily with 1-4 tablets, each having 10-100 mg of MA-1, about 1 to about It can be expected that the patient's symptoms will improve within 12 weeks.

Typical unit dosage forms are size 0 or size 1 capsules comprising anhydrous lactose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate with 10, 20, 50 or 100 mg of MA-1. Can be. It is recommended to store away from moisture and sunlight at 15 to 20 ° C.

MA-1 may also be formulated in a controlled, eg, delayed, sustained or pulsatile release form. MA-1 may also be administered concurrently with other drug therapies, including but not limited to other antidepressant drug therapies or other drug therapies for treating other emotional disorders. Thus, for example, the present invention encompasses administering MA-1 or MA-2 in combination with other melatoninogenic agonists or other sleep inducers. Other antidepressant agents include, but are not limited to, agents in the following drug categories:

Melatonin agonists

Selective Serotonin Reuptake Inhibitor (SSRI)

5-HT _1A antagonist

5-HT _1A / β-adrenoceptor antagonists

5-HT _1B antagonist

5-HT _2C antagonist

     : Optional and non-selective

5-HT _2C agonist

5-HT ₆ agonist

 Α-2 adrenergic antagonists

Serotonin and norepinephrine reuptake inhibotor (SNRI)

Monoamine oxidase inhibitor (MAOI)

Tricyclic antidepressant (TCA)

Triple monoamine reuptake blocker

Benzodiazepin

NMDA receptor antagonists

-Pyrrolinone

-Benzothiadiazide

-Benzoylpiperidine

-Biallylopropylsulfonamide

Metabotropic glutamate receptor (mGluR)

GABA antagonists

NK1 antagonists

NK2 antagonists

CRF1 antagonists

Arginine vasopressin V1b antagonist

MCH receptor antagonists

NGF antagonists

BDNF antagonists

NT-3 antagonists

NT-4 antagonist

CREB antagonists

Examples of such agents include, but are not limited to:

Melatoninic agonists: melatonin, agomelatine, (1R-trans) -N-[[2- (2,3-dihydro-4-benzofuranyl) cyclopropyl] methyl] propanamide and N- [1- (2,3-dihydrobenzofuran-4-yl) pyrrolidin-3-yl] -N-ethylurea], ramelteon, 2-phenylmelatonin, 8-M-PDOT, 2-iodo Melatonin, 6-chloromelatonin;

Serotonin reuptake inhibitors: paroxetine, fluoxetine, sertraline, venlaxafine, citalopram, escitalopram, fluvoxamine, trazadone, nefazodone (nefazodone), milnacipran, desipramine, duloxetine, YM992;

SSRI / 5-HT1A antagonist: WAY-100635, Pindolol;

SSRI / 5-HT1B antagonist: SB-224289;

SSRI / 5-HT2C antagonist;

  Optional: SB242084, RS102221;

  Non-selective: Ketanserin, Irindalone;

SSRI / 5-HT2C agonists: Org 37684, Ro 60-0175, WAY-161503, YM348, WAY-629, WAY-163909;

SSRI / 5-HT6 agonists: LY586713, WAY-466, WAY-1811187;

α-2 adrenergic antagonists: Mirtazapine (Remeron);

Triple monoamine reuptake blocker: DOV 21,947;

NMDA receptor antagonists: MK-801, Memantine, Ketamine, Felbamate, Glycine, D-serine, D-cycloserine, L-glutamate, Ifenprodil;

Pyrrolidion: Piracetam, Aniracetam;

Tricyclic: Amitriptyline, Clomipramine, Desipramine, Dosipine, Dothipine, Doxepin, Imipramine, Lofepramine ), Nortriptyline, Protriptyline, Trimipramine, Iprindole, Oppipramol;

Tetracyclic: Maprotiline, Mianserin, mirtazapine, Amoxapine, Trazodone, nefazodone;

Serotonin reuptake enhancers: tianeptine;

Monoamine Oxidase Inhibitors: Harrmaline, Nialamide, Selegiline, Isocarboxazid, Iproniazid, Iprolozide, Moclozide Moclobemide, Penelzine, Toloxatone, Tranylcypromine;

Dopamine reuptake inhibitors: Bupropion, Amineptine, Methylphenidate, Phenmetrazine, Banoxerine;

Norepinephrine reuptake inhibitors: Atomoxetine, Reboxetine, Reloxazine, Viloxazine, Maprotiline, Bupropion, Reboxetine;

Serotonin-norepinephrine reuptake inhibitors: Desipramine, Duloxetine, Milnacipran, Nefazodone, Venlafaxine;

Benzothiadiazide: cyclothiazide;

Benzoylpiperidine: CX516, CX546;

Biarylopropylsulfonamides: LY392098, LY404187, LY451646;

Metabotropic glutamate receptor (mGluR): 2-methyl-6- (phenylethynyl) -pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] -pyridine (MTEP), JNJ16259685, CPCOOEt, MGS0039, LY341495, LY354740, ACPT-1 / L-SOP (L-serine-O-phosphate), HomoAMPA, N-phenyl-7- (hydroxyimino) cyclopropa [b Chromen-1a-carboxamide;

GABA antagonists: CGP36742, CGP56433, CGP56999;

NK1 antagonists: GW823296, GW679769, GW597599 (Vestipitant), R673, CP-122,721, L-759274, GR205171, L733060;

NK2 antagonist: SR48968;

CRF1 antagonists: DMP696, DMP904, GW876008, AAG561, TS-041, CP-154,526 (antalarmin), SSR125543, R278995 / CRA0450, R121919;

Arginine vasopressin V1b antagonist: SSR149415;

MCH receptor antagonist: T-226296.

In some patients, it has been reported to be useful for increasing antidepressant treatment in combination with lithium or triiodothyronine.

Thus, in another exemplary embodiment, the present invention includes a kit comprising one or more pharmaceutical dosage units of MA-1 or MA-2 and one or more pharmaceutical dosage units of antidepressant, wherein MA-1 Or either or both of the MA-2 unit dosage form and the antidepressant unit dosage form may also comprise antidepressants or antipsychotics, and optionally one or more pharmaceutically active additional ingredients, respectively. In another embodiment, the present invention comprises administering MA-1 or MA-2 and other agent (s) at different time intervals, wherein each effective amount is maintained at a suitable amount at a suitable time in the bloodstream of the patient. Such kits may facilitate the administration of MA-1 or MA-2, for example, ingested over other agent (s) at different time intervals. In related embodiments, the kit comprises a pharmaceutical dosage unit of one agent alone and another pharmaceutical dosage unit comprising both agents. In this way, for example, MA-1 or MA-2 may be taken alone during the day and in combination with other agent (s) in the evening.

When used in this combination, the dosage of each agent is expected to be approximately equal to or less than the effective amount of each agent alone. For example, each pharmaceutically active ingredient can be administered in a dosage of about 20% to about 80% of the dosage when each ingredient is administered alone.

The two (or more) agents may be administered to some degree simultaneously, ie, at the same time (eg, within 0 to about 5 minutes, preferably within about 1 minute of each other), or at different times. For example, in one aspect, the invention is a pharmaceutical composition comprising both an antipsychotic agent and the other agent (s). This embodiment includes, for example, a pill or capsule in which both pharmaceutically active ingredients are mixed together or where each pharmaceutically active ingredient is in a separate portion of the pill or capsule.

In addition, the unit dosage form of the present invention, whether including MA-1 or MA-2 or an active metabolite thereof as the only pharmaceutically active ingredient or in combination with other agents such as antipsychotics or antidepressants, For example, in a sustained, sustained or pulsatile release form. When combined in this form, MA-1 or MA-2 or an active metabolite thereof may be released at the same or different rate and time as the other agent (s).

The following examples are illustrative, not limiting, and illustrate the utility of MA-1 in the prevention or treatment of depressive disease symptoms.

Examples 1 to 3. MA-1 was tested in the following three models: (1) stress-induced cGMP increase, (2) mouse forced swimming test, and (3) rat forced swimming test. The following are the protocols used and the results obtained from this study.

Increased cGMP in stress-induced cerebellum

Protocol: The animals were placed in an impact chamber with an iron grid bottom and impacted at 1 mA for 10 seconds. One minute after the stress, the animals were placed in plastic restraint tubes and sacrificed by electromagnetic radiation (1.8 seconds at 3.5 kW). The cerebellum was quickly removed, rapidly frozen and stored at -80 ° C prior to cGMP analysis. Unstressed animals were taken directly from us, sacrificed by electromagnetic radiation, and tissues were processed in a similar manner. Medication was taken 30-60 minutes before foot shock stress. For cGMP analysis, tissue was homogenized with 2 ml of 1% perchloric acid using Brinkman Polytron set at # 5 for about 15 seconds and left on ice until all samples were homogenized. The samples were then placed in an 85 ° C. water bath for 5 minutes, centrifuged at 2,500 G for 15 minutes, and ˜0.5 mL of supernatant was collected for analysis. Supernatants were diluted 1:20 in sodium acetate buffer according to the instructions of the 125I-cGMP flashplate manufacturer. Diluted samples were incubated overnight in a flashplate well with 125 I-cGMP, and then analyzed with a gamma-counter plate reader, and into the pmol cGMP / mg tissue using standard curves generated in the same experiment. Converted.

RESULTS: Rats subjected to electric shock showed an increase of ˜2.5 × cGMP levels in cerebellum. The increase was attenuated ˜50% by treatment with MA-1 at a 0.1-10 mg / kg dose. The effect was shown to be maximum without dose-response, but lower doses were not attempted.

Mouse forced swimming test

Protocol: Animals maintained a 12:12 LD cycle and lit at 06:00. Mice were placed in the laboratory at least 1 hour before the start of the test. The vehicle, amitriptyline and MA-1 were administered under one of the following three conditions: A) Acute treatment, animals were taken 30 minutes prior to testing; B) 4 days of subchronic morning treatment, doses were taken during the early morning period (09: 00-11: 00 hours), and the last dose was taken 30 minutes before the test; And C) subchronic afternoon treatment, the dose was taken during the evening period (17: 30-18: 00 o'clock, just before extinguishing) and the forced swimming test was performed the next morning. Animals were subjected to a forced swim test using a modification of the protocol originally disclosed by Forsault et al. (Porsolt et al. (1978)). Mice were placed in a 1 L beaker (KIMAX # 14005) filled with 800 ml of water (20-22 ° C.) for 7 minutes of swimming. Animals were scored during the last 5 minutes of the test and assigned "0" if they were actively swimming and "1" if they were not moving except for the small movements needed to keep them floating. The scores were scored for 10 30-second intervals for each mouse over the 5-minute scoring period, with a total possible score of 0-10. Data reported as median (quartile range). Each study was performed independently using a separate group of intact mice. Data was analyzed using Statview, SAS, Cary, NC with Kruskal-Wallis analysis, and then Mann-Whitney U with significance level set at p <0.05. -The test was carried out.

Results: MA-1 was tested for (A) acute treatment, 30 minutes after dosing, (B) 4 days of subchronic therapy, in the morning, 30 minutes after the last dose, and (C) 4 days of subchronic therapy, Efficacy in the mouse forced swimming model was examined under three conditions including dose in the afternoon and test the next morning. Amitriptyline was used as a positive control in this assay and was active under A and B conditions but did not show activity under C conditions. However, MA-1 did not show activity in this assay under any of the conditions tested.

Rat forced swimming test

Protocol: Animals were subjected to a forced swim test using the protocol originally disclosed by Forsault et al. (Eur. J. Pharmacol., 47, 379-391, 1978). Rats were placed in a cylinder (height = 40 cm, diameter = 20 cm) containing 13 cm water (25 ° C.) for 15 minutes each on the first day of the experiment (session 1), and then placed back into the water for 5 minutes after 24 hours. (Session 2). The period of inactivity during the 5 minute test was measured. Six rats per group were examined. The test was performed blind. Session 1 and Session 2 were performed between bright cycles, 2.5 and 5.5 hours after lighting, or dark cycles, 2.5 to 5.5 hours after lighting. Thus, a check during a bright cycle was performed between 9:30 am and 12:30 pm, and a check during a dark cycle was performed between 14:30 pm and 17:30 pm because of the shift of the bright cycle. It was.

In order for the two phase experiments (bright phase and dark phase) to be performed by the same experimenter on the same day, the animals examined during the dark phase should undergo bright cycle transitions before 12 days of the first session of the forced swimming test. , Which led to a 7 hour advance of the light / dark cycle (lit: 0:00 am, extinguished: 12:00 pm). The 12 day period was estimated to be sufficient for dark cycle animals to adapt to metastasis. To tame rats to bright cycle transition, dark cycle animals were subject to metastasis 12 days prior to session 1. To ensure other similar conditions between the light cycle and dark cycle animals, all animals used in this experiment came from the same delivery batch and were kept at the same time, i.e. 12 days before session 1 Put on.

Inspection during the bright phase was performed under normal laboratory light, and inspection during the dark phase was under infrared illumination. MA-1, agomelatine and melatonin were evaluated by two oral (p.o.) doses of two doses (24 hours and 1 hour prior to Session 2), respectively. The first dose was given immediately after session 1. Imipramine (64 mg / kg p.o.) administered twice under the same experimental conditions was used as reference.

Results: To investigate the potential for sensitivity to circadian times, rats were dosed and tested during either the dark phase (Table 1) or the bright phase (Table 2) in a 24-hour cycle. Compounds tested were positive controls imipramine (64 mg / kg), melatonin (10 and 50 mg / kg), agomelatine (10 and 50 mg / kg) and MA-1 (1 and 10 mg / kg) Included. The dose was chosen to match the range reported in the literature for this behavioral analysis or other behavioral analysis. Activity was more pronounced during the dark phase for all melatonin agonists, and agomelatine was shown to have a 60% and 33% reduction in immobility time at 10 and 50 mg / kg, respectively. MA-1 also decreased 37% and 41% immobility times at 1 and 10 mg / kg, respectively, showing a significant decrease in immobility time on both dose tests. Activity was also observed in animals examined during the bright phase (Table 2), but the effect was not significant and there was a lack of agreement according to the doses tested.

Effect of agomelatine, MA-1, melatonin and imipramine on behavioral despair test (dark cycle) in rats (6 rats per group) Treatment (mg / kg) p.o. -24 hours and -60 minutes Float duration in seconds Mean ± s.e.m. p value % Change from control Carrier # 1  210.0 ± 5.6 - - Agomelatine (10) agomelatine (50)  84.8 ± 8.2 *** 140.2 ± 19.1 * <0.0001 0.0107 -60% -33% MA-1 (1) MA-1 (10) # 2  133.0 ± 6.6 *** 124.8 ± 18.8 ** <0.0001 0.0024 -37% -41% Melatonin (10) Melatonin (50)  132.8 ± 16.5 ** 166.8 ± 16.6 * 0.0028 0.0492 -37% -21% Imipramine (64)  63.0 ± 11.1 *** <0.0001 -70%

Student's t test : * = p <0.05; ** = p <0.01; *** = p <0.001

# 1: Escape (1/6)

# 2: death (1/6)

Effect of agomelatine, MA-1, melatonin and imipramine on behavioral despair test (light cycle) in rats (6 rats per group) Treatment (mg / kg) p.o. -24 hours and -60 minutes Float duration in seconds Mean ± s.e.m. p value % Change from control Carrier  168.3 ± 14.1 - - Agomelatine (10) agomelatine (50)   97.8 ± 13.5 ** 191.0 ± 9.4 NS 0.0047 0.2114 -42% + 13% MA-1 (1) MA-1 (10)  145.3 ± 26.0 NS 126.3 ± 26.9 NS 0.4548 0.1967 -14% -25% Melatonin (10) Melatonin (50)  101.3 ± 18.8 * 167.7 ± 10.8 NS 0.0172 0.9709 -40% 0% Imipramine (64)   49.5 ± 10.6 *** <0.0001 -71%

Student's t test : NS = not significant; * = p <0.05; ** = p <0.01; *** = p <0.001

CONCLUSION: This study set was designed to test whether MA-1 shows similar activity to other melatonin agonists in the behavioral stress model and the behavioral despair model of rodents. In these models where other melatonin agonists were active, MA-1 was active. Melatonin and agomelatine are known to be active in stress-induced cGMP assays at levels similar to those observed for MA-1 (data not shown). In addition, MA-1 showed activity in rat FST (Porsolt labs) in a size similar to that seen in agomelatine and melatonin. MA-1 did not show activity in mouse FST, but we did not see activity with other melatonin agonists in this assay. Compared to the rat assay performed by Forsault Laboratories, ineffectiveness in mouse FST is not simply due to species differences, because we believe that for different versions of rat FST, melatonin agonists This is because no activity was observed. This suggests that minor differences in assay design, route of administration or time of administration may be critical for the melatonin agonist to work in the assay. In another study not reported herein, MA-1 underwent a modified forced swim test at 5 mg / kg and 10 mg / kg in rats and showed no effect on immobilization, swimming or climbing, which was statistically It is different from the carrier.

Claims (4)

A method for treating one or more depressive diseases or symptoms thereof in an animal comprising administering to the animal an effective amount of MA-1 or MA-2. The method according to claim 1, Said depressive disorder is selected from the group consisting of major depression, dysthymia, mood swings, and combinations thereof. The method according to claim 1, The symptoms may include persistent sadness, anxiety or empty mood; Feeling hopeless; Pessimism; Guilt, sense of worthlessness, helplessness; Loss of interest or pleasure in past hobbies or activities, including sexual desire; Loss of vitality, fatigue, slowing; Difficulty concentrating, remembering, and making decisions; Insomnia, wheezing at dawn or oversleeping; Appetite and / or weight loss or overeating and weight gain; Thoughts of death or suicide; Attempt to commit suicide; Failure to calm; impatience; Persistent physical symptoms that do not respond to treatment, such as headaches, digestive system diseases, and chronic pain; And any combination thereof. The method according to any one of claims 1 to 3, The method further comprises administering a second antidepressant drug.